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Background

5-FU based chemoradiation prior to total mesorectal excision (TME) followed by additional 5-FU chemotherapy is the standard of care for locally advanced rectal cancer.

The German rectal trial demonstrated a benefit to preoperative chemoradiotherapy with infusional 5-FU and 50.4 Gy, compared with the same regimen given post-operatively. Benefits to preoperative therapy in the German trial included higher rates of sphincter-sparing procedures, decreased acute and long term toxicity, and improved local control rates.

The results of the German trial were published during the accrual of the current trial, which explains why patients were accrued in the adjuvant and then neo-adjuvant setting.

The oral fluoropyrimidine Capecitabine has been shown to be as effective as 5-FU/leucovorin in the adjuvant treatment of Stage III colon cancer, and non-inferior to infusional 5-FU in combination with Oxaliplatin as first line treatment for metastatic colon cancer.

Furthermore, Capecitabine has radiosensitizing properties that make it an attractive alternative to 5-FU in the treatment of rectal cancer.

Whether Capecitabine can replace infusional 5-FU for locally advanced rectal cancer has not been established in a randomized Phase III trial.

This study was conducted as a non-inferiority phase III trial investigating chemoradiation with Capecitabine in comparison with 5-FU in both the pre-operative and post-operative setting.

Methods

The study enrolled patients at least 18 years of age with locally advanced rectal cancer, defined as International Union Against Cancer (UICC) Stages II or III (T3/4 or N+) disease, 0-16 cm from the anal verge. Staging was by endoscopic ultrasound (EUS).

The study was designed as a two-arm, two-strata, randomized phase-III trial.

The 2 arms of the study were capecitabine (Arm A) and 5-FU (Arm B), and the 2 strata were adjuvant (S1) and neo-adjuvant (S2).

The dose of Capecitabine given concurrent with RT was 1,650 mg/m2, and the dose of adjuvant Capecitabine was 2,500 mg/m2. The dose of 5-FU concurrent with RT was 225 mg/m2 continuous infusion daily in the adjuvant setting, whereas in the neoadjuvant setting it was 1000 mg/m2 on days 1-5 and days 29-33. Bolus 5-FU dose was 500 mg/m2.

The primary endpoint was 5-year overall survival, and this was designed as a non-inferiority study. Secondary endpoints were disease-free survival and toxicity.

Results

230 patients were enrolled in the adjuvant stratum, and 161 in the neo-adjuvant stratum.

The Capecitabine and 5-FU arms were well balanced, with about 80% of patients having T3 or T4 tumors, and 60% having node positive disease in each arm.

The percentage of patients receiving all scheduled cycles of chemotherapy in the adjuvant setting was high in both arms, approximately 80%; in contrast, after neo-adjuvant chemoradiation and surgery, 35% of patients did not start post-operative adjuvant therapy, and less than half received all planned cycles.

Toxicity:

Leukopenia was more common in the 5-FU arm.

GI toxicity was greater in the Capecitabine arm, with proctitis developing in 31 Capecitabine patients and 10 5-FU patients, and diarrhea being more pronounced in Capecitabine patients during concurrent chemoRT.

Hand foot skin reaction was significantly more common in the Capecitabine arm, as was fatigue.

Focusing on the neo-adjuvant stratum, the rate of sphincter-sparing surgery was similar between the 2 arms.

More patients in the Capecitabine arm had a pathologic complete response (pCR) rate compared to 5-FU arm: 14% versus 5%, although this did not reach statistical significance (p = 0.16)

There was a trend towards improved T and N downstaging in patients receiving Capecitabine, with less ypN+ tumors (p=0.09).

The rates of local recurrence were low for both arms, 6% for Capecitabine and 7% for 5-FU.

There were fewer distant metastases in the Capecitabine arm, 19% versus 28% (p=0.04).

Hand foot skin (HFS) reaction has been shown to be a marker of good prognosis, and in this study, patients developing any HFS reaction to Capecitabine had better 3-year DFS and 5-year OS compared to those who did not.

Authors' conclusions

Both 5-FU and capecitabine are well tolerated, with GI toxicity and HFS reaction more common with capecitabine.

In the neo-adjuvant setting, capecitabine led to increased surgical downstaging and a higher pCR rate, although this did not reach significance.

Capecitabine was non-inferior to 5-FU with regard to 5-year OS, and showed a strong trend towards improved 5-year OS; 3 year DSF was significantly better with capecitabine.

The development of HFS reaction has prognostic significance.

Capecitabine may replace 5-FU in the peri-operative treatment of locally advanced rectal cancer.

Clinical/Scientific Implications

This study firmly establishes that Capecitabine is at least equivalent, if not slightly superior, to 5-FU in the neo-adjuvant and adjuvant treatment of locally advanced rectal cancer.

In particular, it appears to lead to improved downstaging (in the neo-adjuvant setting), fewer distant metastases, and improved DFS relative to 5-FU.

In practice, many clinical trials subsequent to this incorporate capecitabine rather than 5-FU in addition to other chemotherapy agents, so it is unclear whether this study will have a dramatic impact on clinical practice.

Capecitabine leads to increased GI toxicity relative to 5-FU, but not to the extent that it compromises the ability of patients to complete their planned cycles of chemotherapy, any more so than with 5-FU.

Nevertheless, in the neo-adjuvant setting, a significant number of patients enrolled in this study did not receive planned adjuvant chemotherapy (capecitabine or 5-FU).

This study confirms that the development of hand-foot skin reaction has prognostic significance, and raises the question of whether chemotherapy dose should be adjusted to produce this surrogate clinical marker.

Oct 4, 2010 - Men with advanced prostate cancer that has resisted prior chemotherapy with docetaxel survive a median 2.4 months longer if they take cabazitaxel instead of mitoxantrone, according to the results of a phase III trial published in the Oct. 2, cancer-themed issue of The Lancet.